An update on the CNS actions of TRH and its analogs

Horita, A.

doi:10.1016/s0024-3205(98)00087-3

Cited by 104 publications

(69 citation statements)

References 44 publications

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“…injection of 50 µg protirelin (Relefact TRH 200/400, Hoechst Marion Roussell), which is one-eighth to a quarter dose of that used diagnostically in the thyrotropin-releasing hormone (TRH) test and well-tolerated in this dosage. Protirelin was given at the beginning of the experiment, thus producing the desired prolactin increase during the period of sexual arousal and orgasm (Garbutt et al 1994, Horita 1998. Consecutive increases of thyroxine and triiodothyronine occur with a certain latency.…”

Section: Pharmacological Prolactin Manipulationmentioning

confidence: 99%

Effects of acute prolactin manipulation on sexual drive and function in males

Krüger

Haake²,

Haverkamp³

et al. 2003

Journal of Endocrinology

126

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The neuroendocrine response to sexual activity in humans is characterized by a pronounced orgasm-dependent increase of plasma levels of prolactin. In contrast to the well-known inhibitory effects of chronic hyperprolactinemia on sexual drive and function, the impact of acute prolactin alterations on human sexual physiology is unknown. Therefore, this study was designed to investigate the effects of acute manipulation of plasma prolactin on sexual behavior.Ten healthy males participated in a single-blind, placebo-controlled, balanced cross-over design. Prolactin levels were pharmacologically increased to high levels (protirelin, 50 µg i.v.) or reduced to low physiological concentrations (cabergoline, 0·5 mg p.o.). Sexual arousal and orgasm were then induced by an erotic film and masturbation. In addition to continuous neuroendocrine and cardiovascular recordings, the quality and intensity of the acute sexual drive, arousal, orgasm and refractory period were assessed by extensive psychometric measures.Administration of cabergoline decreased prolactin levels and significantly enhanced all parameters of sexual drive (P,0·05), function (P,0·01) and positive perception of the refractory period (P,0·01). Administration of protirelin increased prolactin concentrations and produced small, but not significant reductions of sexual parameters. The sexual effects observed from cabergoline were completely abrogated by coadministration of protirelin.Although different pharmacological sites of action of prolactin-altering drugs have to be considered, these data demonstrate that acute changes in prolactin plasma levels may be one factor modulating sexual drive and function. Therefore, besides a neuroendocrine reproductive reflex, a post-orgasmic prolactin increase may represent one factor modulating central nervous system centers controlling sexual drive and behavior. These findings may offer a new pharmacological approach for the treatment of sexual disorders.

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Section: Pharmacological Prolactin Manipulationmentioning

confidence: 99%

Effects of acute prolactin manipulation on sexual drive and function in males

Krüger

Haake²,

Haverkamp³

et al. 2003

Journal of Endocrinology

126

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“…All members of the M1 family are aminopeptidases, except for pyroglutamyl peptidase II (PPII, EC 3.4.19.6), a membrane-bound omegapeptidase that catalyzes the inactivation of the neuropeptide thyrotropin-releasing hormone (TRH, ϽGlu-His-Pro-NH 2 ) in the extracellular space (8 -12). TRH is a neurohormone that regulates adenohypophysial secretions and a neurotransmitter with effects on multiple central nervous system functions, including cognition and locomotion (13)(14)(15)(16)(17). Clinical studies have reported beneficial effects of its administration in several diseases, but these improvements are of short duration.…”

mentioning

confidence: 99%

Homology Modeling and Site-directed Mutagenesis of Pyroglutamyl Peptidase II

Chávez‐Gutiérrez¹,

Matta‐Camacho²,

Osuna³

et al. 2006

Journal of Biological Chemistry

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“…Based on its central nervous system effects, TRH has been found to have potential use in the treatment of brain and spinal injury (18,19) and several central nervous system disorders, including spinocerebellar degeneration, cognitive deficits, and spinal cord pain transmission (16,17). The mechanisms by which TRH improves these conditions are not fully elucidated but appear to involve the potentiation by TRH of other neurotransmitter systems.…”

mentioning

confidence: 99%

Kinetic Investigation of the Specificity of Porcine Brain Thyrotropin-releasing Hormone-degrading Ectoenzyme for Thyrotropin-releasing Hormone-like Peptides

Kelly¹,

Slator²,

Tipton³

et al. 2000

Journal of Biological Chemistry

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Evidence indicates that neuronally released thyrotropin-releasing hormone (TRH) is selectively inactivated by TRH-degrading ectoenzyme (TRH-DE) (EC 3.4.19.6). TRH-DE inhibitors may be used to enhance the therapeutic actions of TRH and to investigate the functions of TRH and TRH-DE in the central nervous system.Although TRH-DE appears to exhibit a high degree of specificity toward TRH, systematic specificity studies, which would facilitate inhibitor design, have not been previously conducted for this enzyme. In this paper we present the first description of TRH-DE specificity across a directed peptide library in which the histidyl (P 1 ) residue of TRH was replaced by a series of amino acids. Peptides were synthesized using standard solid phase chemistry. Kinetic parameters were measured either by continuous or discontinuous fluorometric assays or by quantitative high pressure liquid chromatography. The P 1 residue was found to influence significantly both the ability of the peptides to bind to TRH-DE, as measured by their K i values, and the ability of TRH-DE to catalyze their hydrolysis. Moderately bulky, uncharged P 1 residues were found to bind preferentially to TRH-DE. Results from this screen provide valuable information for the development of TRH-DE inhibitors and have led to the identification of two potent, reversible TRH-DE inhibitors, L-pyroglutamyl-L-asparaginyl-L-prolineamide (K i ‫؍‬ 17.5 M) and Glp-AsnPro-7-amido-4-methyl coumarin (K i ‫؍‬ 0.97 M). Thyrotropin-releasinghormone-degrading ectoenzyme (TRH-DE) 1 (EC 3.4.19.6) is a type II cell surface peptidase located on synaptosomal membranes in the central nervous system (1Ϫ4). TRH-DE catalyzes the hydrolysis of the Glp-His bond in thyrotropin-releasing hormone (TRH), a tripeptide with the amino acid sequence L-pyroglutamyl-L-histidyl-L-prolineamide (Glp-His-ProNH 2 ) (5Ϫ10). This enzyme is strategically placed to play a significant role in extracellular inactivation of TRH, and current evidence strongly indicates that TRH-DE is the principal enzyme responsible for terminating the actions of neuronally released TRH (11Ϫ14).Although first recognized as a hypothalamic regulatory hormone, TRH is now believed to function as a neurotransmitter and/or neuromodulator within the central nervous system (15, 16) where it displays a broad spectrum of stimulatory actions independent of its neuroendocrine functions (15Ϫ17). Based on its central nervous system effects, TRH has been found to have potential use in the treatment of brain and spinal injury (18,19) and several central nervous system disorders, including spinocerebellar degeneration, cognitive deficits, and spinal cord pain transmission (16,17). The mechanisms by which TRH improves these conditions are not fully elucidated but appear to involve the potentiation by TRH of other neurotransmitter systems. Despite its promise, the use of TRH as a therapeutic agent is critically undermined by its susceptibility to proteolytic degradation (20).Compounds that potently and selectively inhibit TRH-DE may be use...

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An update on the CNS actions of TRH and its analogs

Cited by 104 publications

References 44 publications

Effects of acute prolactin manipulation on sexual drive and function in males

Effects of acute prolactin manipulation on sexual drive and function in males

Homology Modeling and Site-directed Mutagenesis of Pyroglutamyl Peptidase II

Kinetic Investigation of the Specificity of Porcine Brain Thyrotropin-releasing Hormone-degrading Ectoenzyme for Thyrotropin-releasing Hormone-like Peptides

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